The Hudson River estuary contains Superfund sites because of PCB, dioxin, and heavy metal contamination and levels of PAHs are elevated in sediments at industrialized and urban sites in the lower estuary. Resistance is one of the potential effects of chronic exposure to these Superfund contaminants on resident feral populations. While resistance may be beneficial in the short term to impacted populations, evolutionary costs may accrue to affected populations and trophic transfer of contaminants may compromise the health of ecological communities. Resistance to cytochrome P4501A1 (CYP1A1) induction has observed in feral fish populations from the Hudson River and other Atlantic coast estuaries that are highly contaminated with Superfund toxicants. In previous studies, we have documented impaired inducibility of CYP1A1 transcription in a sentinel, Atlantic tomcod (Microgadus tomcod) from the Hudson River, that are treated with halogenated aromatic hydrocarbon compounds (PCBs and 2,3,7,8-TCDD), but not with non-halogenated PAHs. This study will focus on the mechanistic bases of non-inducibility of CYP1A1 in tomcod that we have observed. Our working hypothesis is that CYP1A1 transcription is inhibited by down-regulation of the aromatic hydrocarbon receptor (AhR) pathway in tomcod and other vertebrate species from Superfund contaminated sites. Because AhR expression is critical to normal liver development and immunosurveillance in the absence of aromatic hydrocarbons, down- regulation of AhR may have profound effects on population and community well-being after remediation of Superfund sites. We will initially determine if impaired inducibility of CYP1A1 is a genetic adaptation or a single generation physiological acclimation. We will use our recently developed tomcod AhR probes to compare the effects of chemical treatment and environmental exposure on expression of AhR mRNA and protein in tomcod from the Hudson River and a cleaner reference river in Canada. Additionally, the epigenetic effects of metals- induced methylation will be investigated on expression of CYP1A1 im tomcod. Previously identified tomcod AhR variants will be characterized and their functional significance evaluated with environmentally relevant concentrations of PCBs and PAHs. Finally, a response of probabilities to Superfund contaminants will be evaluated. These studies will provide new insights into the susceptibilities of feral populations to the toxic effects of mixtures of Superfund chemicals.